This invention relates to an improved process for preparing potassium clavulanate, a novel crystalline form of potassium clavulanate and the use thereof in treating bacterial infections.
Clavulanic acid and its salts are disclosed in British Patent No. 1508977 as xcex2-lactamase inhibitors capable of enhancing the antibacterial effectiveness of xcex2-lactam antibiotics such as penicillins and cephalosporins against many xcex2-lactamase producing bacteria. Antibacterial compositions comprising potassium clavulanate and amoxycillin are commercially available under the trade name xe2x80x98Augmentinxe2x80x99 (registered Trademark of SmithKline Beecham Corporation), and certain oral dry unit-dose antibacterial compositions of potassium clavulanate and amoxycillin are described in British Patent No. 2005538. Antibacterial compositions comprising potassium clavulanate and ticarcillin are commercially available under the trade name xe2x80x98Timentinxe2x80x99 (registered Trademark of SmithKline Beecham Corporation). Potassium clavulanate may also be formulated with other penicillins and cephalosporins to enhance their antibacterial efficacy, and also may be formulated alone for separate co-administration with penicillins and cephalosporins.
British Patent No. 1508977 also discloses that salts of clavulanic acid can be obtained by absorbing the clavulanate anion in filtered broth onto an anion exchange resin, eluting therefrom with an electrolyte, desalting the resulting solution, applying the desalted solution to a further anion exchange resin, chromatographically eluting therefrom with an electrolyte, desalting the resulting solution and thereafter removing the solvent. This process can be used to give acceptable yields of pure material, but the use of resin columns involves significant investment and they can introduce limitations in large scale production operations.
British Patent No. 1543563 discloses a process for the preparation of clavulanic acid salts via precipitation by lithium carbonate.
In European Patent No. 0026044, the use of the tertiary-butylamine salt of clavulanic acid as an intermediate in the preparation of clavulanic acid and pharmaceutically acceptable salts and esters thereof as well as a process for the preparation of clavulanic acid or a pharmaceutically acceptable salt or ester thereof comprising converting the tertiary-butylamine salt of clavulanic acid into clavulanic acid or a pharmaceutically acceptable salt or ester thereof are described. The tertiary-butylamine salt of clavulanic acid, which can be obtained in high purity, has been disclosed in Belgian Patent No. 862211, but only as a suitable ingredient for pharmaceutical formulations. European Patent No. 0026044 further discloses a process for the purification of clavulanic acid or a pharmaceutically acceptable salt or ester thereof which comprises contacting impure clavulanic acid in an organic solvent with tertiary-butylamine, isolating the tertiary-butylamine salt of clavulanic acid, and converting the thus formed tertiary-butylamine salt into calvulanic acid or a pharmaceutically acceptable salt or ester thereof.
Crystalline potassium clavulanate generally exists in the form of rod-like or needle-like crystals, which are generally relatively large, long crystals, sometimes agglomerated into plate-like crystals, and sometimes randomly aggregated into loosely formed bundles. This form of potassium clavulanate can give rise to processing difficulties in that the material does not always flow readily, is of low bulk density, and can be difficult to sieve. U.S. Pat. No. 5,288,861 describes crystalline potassium clavulanate in the form of crystalline rosettes, each comprising a plurality of needle crystals radiating out from a common nucleation point. Such rosette form of crystalline potassium clavulanate has improved flow characteristics and sieving characteristics as compared with the standard needle form potassium clavulanate, thus resulting in advantageous pharmaceutical processing and formulation. Crystalline potassium clavulanate may also exist in a more open rosette, or starburst, form as described in U.S. Pat. No. 5,288,861.
This invention relates to an improved process for the preparation of potassium clavulanate of the formula (I): 
directly from the tertiary-butylamine salt of clavulanic acid which results in greater overall yield and better final product quality than the prior art processes.
The present invention also relates to a new rosette-like starburst crystalline form of potassium clavulanate.